Nusbiarylins inhibit transcription and target virulence factors in bacterial pathogen staphylococcus aureus

Adrian Jun Chu, Yangyi Qiu, Rachel Harper, Lin Lin, Cong Ma (Corresponding Author), Xiao Yang

Research output: Journal article publicationJournal articleAcademic researchpeer-review

1 Citation (Scopus)

Abstract

The emergence of multidrug resistance in the clinically significant pathogen Staphylococcus aureus is a global health burden, compounded by a diminishing drug development pipeline, and a lack of approved novel antimicrobials. Our previously reported first-in-class bacterial transcription inhibitors “nusbiarylins” presented a promising prospect towards the discovery of novel antimicrobial agents with a novel mechanism. Here we investigated and characterised the lead nusbiarylin compound, MC4, and several of its chemical derivatives in both methicillin-resistant S. aureus (MRSA) and the S. aureus type strains, demonstrating their capacity for the arrest of growth and cellular respiration, impairment of RNA and intracellular protein levels at subinhibitory concentrations. In some instances, derivatives of MC4 were also shown to attenuate the production of staphylococcal virulence factors in vitro, such as the exoproteins α-toxin and Panton–Valentine Leukocidin (PVL). Trends observed from quantitative PCR assays suggested that nusbiarylins elicited these effects possibly by acting via but not limited to the modulation of global regulatory pathways, such as the agr regulon, which coordinates the expression of S. aureus genes associated with virulence. Our findings encourage the continued development of more potent compounds within this novel family of bacterial transcription inhibitors.

Original languageEnglish
Article number5772
Pages (from-to)1-18
Number of pages18
JournalInternational Journal of Molecular Sciences
Volume21
Issue number16
DOIs
Publication statusPublished - 2 Aug 2020

Keywords

  • Antibiotic
  • Antimicrobial agent
  • Drug discovery
  • MRSA
  • Nusbiarylin
  • Staphylococcus aureus

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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